In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor β1 (pCMV-TGF-β1) prevents the development of T helper cell type 1 (Th1)-mediated experimental colitis induced by the haptenating reagent, 2,4,6-trinitrobenzene sulfonic acid (TNBS). In addition, such plasmid administration abrogates TNBS colitis after it has been established, whereas, in contrast, intraperitoneal administration of rTGF-β1 protein does not have this effect. Intranasal pCMV-TGF-β1 administration leads to the expression of TGF-β1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-β1–producing T cells and macrophages in these tissues, and is not associated with the appearances of fibrosis. These cells cause marked suppression of interleukin (IL)-12 and interferon (IFN)-γ production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor β2 (IL-12Rβ2) chain expression. Coadministration of anti–IL-10 at the time of pCMV-TGF-β1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFN-γ secretion. However, anti–IL-10 leads to increased tumor necrosis factor α production, especially in established colitis. Taken together, these studies show that TGF-β1 inhibition of a Th1-mediated colitis is due to: (a) suppression of IL-12 secretion by IL-10 induction and (b) inhibition of IL-12 signaling via downregulation of IL-12Rβ2 chain expression. In addition, TGF-β1 may also have an inhibitory effect on IFN-γ transcription.
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3 July 2000
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June 26 2000
Treatment of Experimental (Trinitrobenzene Sulfonic Acid) Colitis by Intranasal Administration of Transforming Growth Factor (Tgf)-β1 Plasmid: TGF-β1–Mediated Suppression of T Helper Cell Type 1 Response Occurs by Interleukin (Il)-10 Induction and IL-12 Receptor β2 Chain Downregulation
Atsushi Kitani,
Atsushi Kitani
aMucosal Immunity Section, Laboratory of Clinical Investigation
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Ivan J. Fuss,
Ivan J. Fuss
aMucosal Immunity Section, Laboratory of Clinical Investigation
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Kazuhiko Nakamura,
Kazuhiko Nakamura
aMucosal Immunity Section, Laboratory of Clinical Investigation
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Owen M. Schwartz,
Owen M. Schwartz
bBiological Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Takashi Usui,
Takashi Usui
aMucosal Immunity Section, Laboratory of Clinical Investigation
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Warren Strober
Warren Strober
aMucosal Immunity Section, Laboratory of Clinical Investigation
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Atsushi Kitani
aMucosal Immunity Section, Laboratory of Clinical Investigation
Ivan J. Fuss
aMucosal Immunity Section, Laboratory of Clinical Investigation
Kazuhiko Nakamura
aMucosal Immunity Section, Laboratory of Clinical Investigation
Owen M. Schwartz
bBiological Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
Takashi Usui
aMucosal Immunity Section, Laboratory of Clinical Investigation
Warren Strober
aMucosal Immunity Section, Laboratory of Clinical Investigation
Abbreviations used in this paper: H and E, hematoxylin and eosin; LP, lamina propria; LPMC, lamina propria mononuclear cell; RT, reverse transcription; SAC, Staphylococcus aureus Cowans; STAT4, signal transducer and activator of transcription 4.
Received:
February 17 2000
Revision Requested:
April 28 2000
Accepted:
May 11 2000
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Exp Med (2000) 192 (1): 41–52.
Article history
Received:
February 17 2000
Revision Requested:
April 28 2000
Accepted:
May 11 2000
Citation
Atsushi Kitani, Ivan J. Fuss, Kazuhiko Nakamura, Owen M. Schwartz, Takashi Usui, Warren Strober; Treatment of Experimental (Trinitrobenzene Sulfonic Acid) Colitis by Intranasal Administration of Transforming Growth Factor (Tgf)-β1 Plasmid: TGF-β1–Mediated Suppression of T Helper Cell Type 1 Response Occurs by Interleukin (Il)-10 Induction and IL-12 Receptor β2 Chain Downregulation. J Exp Med 3 July 2000; 192 (1): 41–52. doi: https://doi.org/10.1084/jem.192.1.41
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